ES2293036T3 - N-ALQUIL-4-METILENAMINO-3-HIDROXI-2-PIRIDONAS AS ANTIMICROBIAL AGENTS. - Google Patents

Abstract

Compounds of Formula (I) are effective in the treatment of a microbial infection.

Description

N-alkyl-4-methylenamino-3-hydroxy-2-pyridones as antimicrobial agents.

Field of the Invention

The invention relates to certain N-alkyl-4-methylenamino-3-hydroxy-2-pyridones useful as antimicrobial agents.

Background of the invention

The chemical and medical literature describes supposedly antimicrobial compounds, that is, capable of destroying or inhibiting the growth or proliferation of microorganisms such as bacteria. For example, such antibacterial agents and other antimicrobial agents are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2nd edition ( 1981).

The mechanisms of action of these agents Antibacterials are variable. A significant mechanism is the bacterial aminopeptidase (bMAP) inhibitors. Inhibition of bMAP is an important therapeutic objective in the area of anti-infective approach because it is involved in the translation of mature proteins and is conserved among pathogenic bacteria known. Therefore, the inhibition of this enzyme should lead to broad spectrum antimicrobial agents.

Many attempts to produce agents More effective antimicrobials lead to ambiguous results. From In fact, few antimicrobial agents are produced authentically clinically acceptable in relation to their spectrum of antimicrobial activity, its ability to avoid microbial resistance and its pharmacology. For all this the permanent need to develop antimicrobial agents of broad spectrum that are effective against microbes resistant.

Patent DE 24 43 714 describes 4-benzyloxy-2 (IH) -pyridones as antimicrobial agents and their manufacturing method.

Summary of the invention

The invention provides compounds that are potent bMAP inhibitors and that are effective for treating microbial infections In particular, the present invention is refers to compounds that have a structure according to formula (I) next:

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one

Another aspect of the invention relates to methods for using the compounds of formula (I) to treat a microbial infection in a subject in need thereof.

Another aspect provides methods to elaborate compounds of formula (I).

Detailed description of the invention I. Terms and definitions

Below is a list of Definitions of the terms used herein:

"Acil" or "carbonyl" is a radical formed by removing the hydroxy group from a carboxylic acid (it is say, R-C (= O) -). Preferred acyl groups they include (eg), acetyl, formyl and propionyl.

"Alquil" is a hydrocarbon chain saturated having 1 to 15, preferably 1 to 10 and more preferably 1 to 4 carbon atoms. "Alkene" is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and that it has from 2 to 15, preferably from 2 to 10 and more preferably from 2 to 4 carbon atoms. "Alquino" is a hydrocarbon chain which has at least one (preferably only one) triple bond carbon-carbon and having 2 to 15, preferably from 2 to 10 and more preferably from 2 to 4 atoms of carbon. The alkyl, alkene and alkyne chains (mentioned in collectively as "hydrocarbon chains") can be linear or branched and substituted or unsubstituted. The chains Preferred branched alkyl, alkene and alkyne have one or two branches, preferably a branch. Preferred chains are the I rent. Each alkyl, alkene and alkyne hydrocarbon chain can be unsubstituted or substituted with 1 to 4 substituents; if they are substituted, preferred chains are monosubstituted, disubstituted or trisubstituted. Hydrocarbon chains alkyl, alkene and alkyne may be substituted, independently from each other, by halo, hydroxy, aryloxy groups (e.g. eg, phenoxy), heteroaryloxy, acyloxy (eg, acetoxy), carboxy, aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioceto, cyano, or any combination thereof. The groups Preferred hydrocarbons include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl and exomethylene.

Here, an alkyl moiety, "lower" alkene or alkyne (eg, "lower alkyl") it is a chain comprising from 1 to 6, preferably from 1 to 4, carbon atoms in the case of the alkyl moiety and from 2 to 6, preferably from 2 to 4, carbon atoms in the case of the moieties alkene and alkyne.

The term "alkoxy" is an oxygen radical with a substituent in the hydrocarbon chain, where the chain hydrocarbon is an alkyl or alkenyl (i.e. -O-alkyl or -O-alkenyl). The groups Preferred alkoxy include (eg), methoxy, ethoxy, propoxy and allyloxy.

"Aril" is a hydrocarbon ring aromatic. Aryl rings are monocyclic ring systems or fused bicyclics. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings They are also called phenyl rings. Aryl rings bicyclics contain 8 to 17 carbon atoms, preferably from 9 to 12 carbon atoms, in the ring. Aryl rings bicyclics include ring systems where a ring is aryl and the other ring is aryl, cycloalkyl or heterocycloalkyl. The Preferred bicyclic aryl rings comprise rings of 5, 6 or 7 members fused to rings of 5, 6 or 7 members. The Rings aryl may not be substituted or substituted with 1 to 4 ring substituents. The aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The aryl ring radical plus Preferred is phenyl.

"Aryloxy" is an oxygen radical that has an aryl substituent (i.e. -O-aryl). The Preferred aryloxy groups include (eg), phenoxy, naphthyloxy, methoxyphenoxy and methylenedioxyphenoxy.

"Cycloalkyl" is a hydrocarbon ring saturated or unsaturated. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic ring systems or bicyclic fused, spiro or bridge. The Rings Monocyclic cycloalkyl contain about 3 to about 9, preferably 3 to 7, carbon atoms in the ring. Bicyclic cycloalkyl rings contain 7 to 17, preferably from 7 to 12, carbon atoms in the ring. The Preferred bicyclic cycloalkyl rings comprise rings of 4, 5, 6 or 7 members that are fused to 5, 6 or 7 rings members. Cycloalkyl rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Cycloalkyl it can be substituted by halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl and cyclohexyl.

"Halo" or "halogen" is fluorine, chlorine, bromine or iodine Preferred halo are fluorine, chlorine and bromine; plus Typically preferred are chlorine and fluorine and especially the fluorine.

"Haloalkyl" is a hydrocarbon chain linear, branched or cyclic substituted with one or more substituents halo. Preferred haloalkyls are C 1 -C 12, more preferred are those C 1 -C 6 haloalkyls and even more preferred they are the C 1 -C 3 haloalkyls. The Preferred halo substituents are fluorine and chlorine. The haloalkyl plus Preferred is trifluoromethyl.

"Heteroatom" is a nitrogen atom, sulfur or oxygen. Groups that contain more than one heteroatom They may contain different heteroatoms.

"Heteroalkyl" is a saturated chain or unsaturated carbon-containing and at least one heteroatom, not never meeting two adjacent heteroatoms. The chains heteroalkyl contain 2 to 15 atoms (carbon and heteroatoms) in the chain, preferably from 2 to 10, more preferably from 2 to 5. For example, alkoxy radicals (ie, -O-alkyl or -O-heteroalkyl) are included in heteroalkyl. Heteroalkyl chains can be linear or branched. Branched heteroalkyl chains Preferred have one or two branches, preferably one branch. The Preferred heteroalkyl chains are saturated. The chains unsaturated heteroalkyl have one or more double bonds carbon-carbon and / or one or more triple bonds carbon-carbon Heteroalkyl chains preferred unsaturated have one or two double bonds or one link triple, more preferably a double bond. The chains heteroalkyl may not be substituted or substituted with 1 to 4 substituents Preferred substituted heteroalkyl chains are monosubstituted, disubstituted or trisubstituted. The chains heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioceto, cyano, or any combination thereof.

"Heteroaryl" is an aromatic ring that contains carbon atoms and 1 to about 6 heteroatoms in the ring Heteroaryl rings are ring systems fused monocyclic or bicyclic. Heteroaryl rings monocyclics contain from about 5 to about 9 atoms (carbon and heteroatoms), preferably 5 or 6 atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 atoms, preferably 8 to 12 atoms, in the ring. The Rings bicyclic heteroaryl include ring systems where a ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Ring systems Preferred bicyclic heteroaryls comprise rings of 5, 6 or 7 members fused to rings of 5, 6 or 7 members. The Rings heteroaryl can be unsubstituted or substituted with 1 to 4 ring substituents. Heteroaryl rings may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof. The Preferred heteroaryl rings include, but not form limiting, the following:

2

3

"Heteroaryloxy" is an oxygen radical that has a heteroaryl substituent (i.e. -O-heteroaryl). Preferred heteroaryloxy groups include (eg), pyridyloxy, furanoyloxy, (thiophene) oxy, (oxazol) oxy, (thiazole) oxy, (isoxazol) oxy, pyrimidinyloxy, pyrazinyloxy and benzothiazolyloxy.

"Heterocycloalkyl" is a saturated ring or unsaturated containing carbon atoms and 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. The Rings heterocycloalkyl are not aromatic. The Rings heterocycloalkyl are monocyclic ring systems or systems of fused bicyclic ring, with bridge or spiro. The Rings Monocyclic heterocycloalkyl contain about 3 to about 9 atoms (carbon and heteroatoms), preferably from 5 to 7 atoms, in the ring. Heterocycloalkyl rings bicyclics contain 7 to 17 atoms, preferably 7 to 12 atoms, in the ring. Bicyclic heterocycloalkyl rings they contain about 7 to about 17 atoms in the ring, preferably 7 to 12 atoms in the ring. The Rings bicyclic heterocycloalkyl may be ring systems fused, spiro or bridge. Heterocycloalkyl rings Preferred bicyclics comprise 5, 6 or 7 member rings fused to rings of 5, 6 or 7 members. The Rings heterocycloalkyl may be unsubstituted or substituted with 1 to 4 substituents on the ring. Chain heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents in the chain heterocycloalkyl include halo and haloalkyl. The Rings Preferred heterocycloalkyl include, but not form limiting, the following:

4

5

6

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"Spirocycle" is a dirradical substituent alkyl or heteroalkyl wherein said dirradical substituent is geminally bound and where said dirradical substituent forms a ring that contains 4 to 8 atoms (carbon or heteroatom), preferably 5 or 6 atoms.

Although the alkyl, heteroalkyl groups, cycloalkyl and heterocycloalkyl may be substituted with hydroxy, amino and amido groups, as mentioned above, The following are not contemplated in the invention:

one.

Enoles (OH attached to a carbon bearing a double link).

2.

Amino groups attached to a carbon that It has a double bond (except for vinyl amides).

3.

Plus of a hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and the three atoms are atoms of a ring heterocycloalkyl);

Four.

Hydroxy, amino or amido attached to a carbon that also has a heteroatom attached to it.

5.

Hydroxy, amino or amido attached to a carbon that also has a halogen attached to it.

A "pharmaceutically acceptable salt" is a cationic salt formed in any acidic group (e.g., acid hydroxamic or carboxylic) or an anionic salt formed in any basic group (eg, amino). Many of these salts are known in the art, as described in the world patent WO-87/05297, granted to Johnston et al. Y published on September 11. Preferred cationic salts include alkali metal salts (such as sodium and potassium) and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides (such as chloride salts), sulfonates, carboxylates, phosphates and the like.

These salts are well known to the expert in matter, which is capable of preparing any salt with the information available in the art. In addition, it is recognized that the skilled in the art may prefer one salt to another for reasons of solubility, stability, ease of formulation and the like. The determination and optimization of these salts is something that is part of the practice of the expert in the field.

A "solvate" is a complex formed by the combination of a solute (eg, a compound of formula (I)) and a solvent (eg, water). See J. Honig et al., The Van Nostrand Chemist's Dictionary , p. 650 (1953). Pharmaceutically acceptable solvents used according to the present invention include those that do not interfere with the biological activity of the compound of the invention (e.g., water, ethanol, acetic acid, N, N-dimethylformamide and others known or readily determined by the expert in the matter).

The terms "optical isomer", "stereoisomer" and "diastereomer" have the standard meanings recognized in the art (see, eg, Condensed Chemical Dictionary of Hawley , 11th Ed.). Examples of specific protected forms and other derivatives of the compounds of the present invention are not intended to be limiting. The application of other protecting groups, salt forms, etc. useful is within reach of the expert in the mate-
estuary.

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II. Compounds

The present invention relates to compounds of formula (I):

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7

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Below is a description of especially preferred remains, although not intended to limit the scope of the claims.

Each R1 is independently selected from hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. In one embodiment, R is hydrogen.

Each R2 is independently selected from hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. In one embodiment, R2 is hydrogen.

R 3 and R 4 are selected, independently of each other, of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl and alkylheterocycloalkyl; or R 3 and R 4, together with the nitrogen atom to which they are bound together to form heteroaryl or heterocycloalkyl moieties, optionally substituted with at least hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and combinations of same.

R 5 and R 6 are selected, independently of each other, of hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl. In one embodiment, R 5 and R 6 are, each One hydrogen.

III. Compound Preparation

The compounds of the invention can be prepared through different procedures. The syntheses especially Preferred are described in the following general reaction scheme. The R groups used to illustrate non-reaction schemes are necessarily related to the respective R groups used to describe the different aspects of the compounds of formula I. That is, p. e.g., R1 in formula (I) no represents the same remainder as R1 here). Specific examples to prepare the compounds of the present invention are included in section VII of this document.

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Scheme general

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8

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In general scheme I, the starting material S1 is known, is made by known methods or is commercial. S1 is protected by subjecting it to an alkylating agent in presence of base in an alcohol-type solvent to produce the compound S2, where "Ar" is defined as an aryl moiety. In herein, "alkylating agent" means an agent which reacts with S1 causing both nitrogen and S1 hydroxyl form a new bond carbon-nitrogen and carbon-oxygen, respectively. Non-limiting examples of an alkylating agent they include halomethylenearyl and halomethyleneheteroaryl. An example of a Alcohol type solvent is methanol. Suitable examples of bases include potassium hydroxide, potassium carbonate, potassium tert-butoxide, sodium methoxide and Triton B.

In turn, S2 is selectively checked out by a hydrogenating agent to obtain S3. At the moment memory, "hydrogenating agent" means atom addition of hydrogen to another atom residue like carbon. Suitable examples of a hydrogenating agent include carbon palladium or rhodium in carbon, in a solvent of methanol type and under gas of hydrogen.

Finally, S3 is formulated and amine by a formilating agent and an aminent agent, respectively. Here, "formilating agent" means an agent that transfers a methylene unit "CH2" or
9 . Non-limiting examples of a formilant agent are paraformaldehyde, formaldehyde, formic acid-formamide, formylimidazole, p-nitrophenyl formate. Alternatively, any aldehyde (R-COH) can be used as a forming agent in this application. The result is that the methylene unit is branched further based on the aldehyde used. These forming agents are marketed or made by known methods. Herein, "amminating agent" means any primary amine of formula NHR 3 or secondary amine of formula NR 3 R 4. These amines are marketed or made by known methods. For example, many of these amines can be identified using the ChemOffice WebServer and ChemACX databases. These amines can be further modified by methods well known in the art.

These stages can be changed to increase the desired product performance. The subject matter expert will know make a judicious choice of reagents, solvents and temperatures as important factors for the success of any synthesis. The determination of the optimal conditions, etc., is a routine matter. In this way the subject matter expert can prepare different compounds using the schemes as a guide previous.

It is recognized that the expert in the art of organic chemistry can easily perform standard manipulations of organic compounds without other guidance; that is, the realization of these manipulations is within the scope and practice of the person skilled in the art. These manipulations include, but are not limited to, the reduction of carbonyl compounds to their corresponding alcohols, the oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherification, esterification and saponification and the like. Examples of these manipulations are discussed in standardized texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (vol. 2) and other texts known to those skilled in the art.

The person skilled in the art will also readily recognize that certain reactions are performed optimally when other potentially reactive functionality is masked or protected in the molecule, thus avoiding unwanted side reactions and / or improving the reaction performance. Often the person skilled in the art uses protective groups to obtain these higher yields or to avoid unwanted reactions. These reactions are described in the literature and are also within the scope of knowledge of the person skilled in the art. Examples of many of these manipulations can be found, e.g. e.g., in T. Greene, Protecting Groups in Organic Synthesis .

The compounds of the invention may have one or more chiral centers. As a consequence, it can be prepared from selectively an optical isomer, including diastereomers and enantiomers, instead, p. eg, using raw materials, chiral catalysts or solvents, or both can be prepared stereoisomers or both optical isomers, including diastereomers and enantiomers at the same time (racemic mixture). Since the compounds of the invention may exist as mixtures racemic, mixtures of optical isomers can be separated, including diastereomers and enantiomers, or stereoisomers using known methods such as chiral salts, chiral chromatography and the like.

In addition, it is recognized that an optical isomer, including diastereomers and enantiomers, or a stereoisomer It may have more favorable properties than others. So when describes or claims the invention, when describing a mixture racemic is clearly considered to be described and claimed also both optical isomers, including diastereomers and enantiomers, or stereoisomers practically free of the rest.

IV. Methods of use

The compounds of the present invention are useful as antimicrobial agents. Without pretending to impose any theory, these compounds could act as ion chelators cobalt of the active site of the bMap. As chelators, these Compounds could act as inhibitors of metalloenzymes.

V. Compositions

The compositions of the invention include:

(to)

a safe and effective amount of a compound of the invention; Y

(b)

a pharmaceutically acceptable vehicle.

Therefore, the compounds of the invention can be formulated in pharmaceutical compositions for use in the treatment of microbial infections. Standard pharmaceutical formulation techniques such as those described in Remington's Pharmaceutical Sciences , Mack Publishing Company, Easton, Pa., Latest edition are used.

A "safe and effective amount" of a compound of formula (I) is an amount that is effective for destroy or suppress the growth or reproduction of microorganisms in an animal, preferably a mammal, more preferably a person, without adverse effects unwanted (such as toxicity, irritation or allergic response) and with a reasonable benefit / risk ratio when used in the form described in the present invention. The "safe amount and effective "specific will obviously vary depending on factors such as, p. eg, the condition that must be treated, the condition patient physics, duration of treatment, nature of concurrent therapy (if any), the specific pharmaceutical form which must be used, the vehicle used, the solubility of the compound of formula (I) of the present invention and the regimen of Desired dosage for the composition.

In addition to the compound of the present invention, the compositions of the present invention contain a vehicle pharmaceutically acceptable. The expression "vehicle pharmaceutically acceptable, "herein means one or more loading diluents or solid encapsulating substances or compatible liquids that are suitable for administration to a animal, preferably a mammal and more preferably a human.  The expression "compatible", herein, means that the components of the composition can be mixed with the compound of the invention and each other so that there is no interaction that could basically reduce effectiveness pharmaceutical composition in ordinary conditions of use. The pharmaceutically acceptable vehicles must logically have a sufficiently high purity and toxicity low enough to be adequate to be administered to the animal, preferably to the mammal and more preferably the human that should be treated.

Some examples of substances that can serve as pharmaceutically acceptable vehicles or components of they are sugars, such as lactose, glucose and sucrose; starches, such as wheat starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; jelly; talcum powder; solid lubricants such as stearic acid and stearate  magnesium; calcium sulfate; vegetable oils, such as peanut, cottonseed oil, sesame oil, olive oil, cereal oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as Tweens®; agents humectants such as sodium lauryl sulfate; coloring agents; flavoring agents; thickeners, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline solution and phosphate buffer solutions.

The choice of vehicles pharmaceutically acceptable to be used together with the compound of the invention is basically determines by the way in which the compound.

If the compound of the invention should be injected, the preferred pharmaceutically acceptable carrier is a sterile physiological saline with a suspending agent compatible with blood with a pH adjusted to approximately 7.4.

In particular, the vehicles pharmaceutically acceptable for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, sulfate calcium, vegetable oils, synthetic oils, polyols, acid alginic, phosphate buffer solutions, emulsifiers, saline Isotonic and pyrogen-free water. Preferred vehicles for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Preferably, the vehicle pharmaceutically acceptable in administration compositions parenteral comprises at least 90% by weight of the composition total.

The compositions of the present invention are preferably provided in unit dosage form. In the present report, a "unit dosage form" is a composition of the present invention containing an amount of a compound of formula (I) that is suitable for administration to an animal, preferably a mammal, more preferably a person, in a single dose in accordance with good practices medical These compositions preferably comprise 5 mg. (milligrams) to 1,000 mg, more preferably 10 mg to 500 mg, more preferably from 10 mg to 300 mg, of a compound of formula (I).

The compositions of the present invention may have any of several suitable forms (eg), for oral, rectal, topical, nasal, ocular or parenteral administration. Depending on the desired route of administration, it can be chosen among the different pharmaceutically acceptable carriers known in the art. These include fillers, diluents, hydrotropes, surfactants and solid or liquid encapsulating substances. Optional pharmaceutically active products may be included that do not practically interfere with the inhibitory activity of the compound of formula (I). The amount of vehicle used with the compound of formula (I) is sufficient to provide a practical amount of product for administration by unit dose of the compound of formula (I). The techniques and compositions for preparing pharmaceutical forms useful for the methods of the present invention are described in the following references, all incorporated herein by reference: Modern Pharmaceutics , chap. 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

Different ways can be used oral pharmaceuticals, including solid forms such as tablets, capsules, granules or powders in bulk. These forms orals comprise a safe and effective amount, usually at minus 5% and preferably 25% to 50%, of the compound of formula (I). The tablets can be treated by compression, crushing, enteric coating, sugar coating, film coating or multiple compression, and can contain binders, lubricants, diluents, disintegrants, colorants, flavorings, fluidizers and fusing agents adequate. Oral liquid pharmaceutical forms include aqueous solutions, emulsions, suspensions, solutions and / or reconstituted suspensions from non-effervescent granules and Effervescent preparations reconstituted from granules effervescent, containing solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, fusing agents, coloring agents and flavoring agents adequate.

Pharmaceutically acceptable vehicles suitable for preparing unit dosage forms for Oral administration are well known in the art. The tablets typically comprise pharmaceutically adjuvants conventional compatible such as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and saccharose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Sliding agents can be used such as silicon dioxide to improve the characteristics of powder mixture flow. Coloring agents can be added, such as FD&C dyes, to improve the appearance. The sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint and fruit aromas are useful adjuvants for chewable tablets. Capsules typically comprise one or more of the solid diluents described above. The selection of vehicle components It depends on secondary considerations such as taste, cost and stability during storage, which are not critical for the purposes of the present invention and can easily be made by the person skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions and the like. The Pharmaceutically acceptable vehicles suitable for preparing These compositions are well known in the art. The Typical vehicle components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For one suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel ™ RC-591, tragacanth and sodium alginate; agents Typical humectants include lecithin and polysorbate 80 and Typical preservatives include methylparaben and sodium benzoate. The oral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and dyes described above.

These compositions can also be coated. by conventional methods, typically with coatings dependent on pH or time, so that the compound of the invention is released in the gastrointestinal tract near the desired topical application or in successive times to extend to the desired action over time. These pharmaceutical forms typically include, but are not limited to, one or more of the following compounds: cellulose acetate phthalate, acetate phthalate of polyvinyl, hydroxypropyl methylcellulose phthalate, ethyl cellulose,  Eudragit2 coatings, waxes and shellac.

The compositions of the present invention They can also include other active ingredients.

Other compositions useful for achieving a systemic administration of the compounds of the present invention They include sublingual, oral and nasal dosage forms. These compositions typically comprise one or more substances of soluble fillers such as sucrose, sorbitol and mannitol; Y binders such as gum arabic, microcrystalline cellulose, carboxymethylcellulose and hydroxypropyl methylcellulose. They can also include sliding agents, lubricants, sweeteners, dyes, antioxidants and flavorings described previously.

The compositions of the present invention they can also be administered topically to the subject, e.g. eg by direct application or dispersion of the composition on the epidermis or the epithelial tissue of the subject, or via transdermal through a "patch." These compositions include, p. eg, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise an amount. safe and effective, usually at least 0.1% and preferably of 1% to 5%, of the compound of formula (I). The right vehicles for topical administration preferably remain on the skin in form of continuous film and not take off from there nor by the effect of perspiration or immersion in water. For the In general, the vehicle is organic in nature and capable of containing the compound of formula (I) in dispersed or dissolved form. He vehicle may include emollients, emulsifiers, thickeners, pharmaceutically acceptable solvents and the like.

SAW. Administration Methods

This invention also provides methods for treat a microbial infection in human or animal subjects by administering a safe and effective amount of a compound of formula (I) to said subject.

The compositions of the present invention They can be administered topically or systemically. The application systemic includes any method to introduce a compound of formula (I) in body tissues, e.g. eg administration transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, Rectal and oral. The compounds of formula (I) of the present invention are preferably administered orally.

The specific dose of inhibitor you should administered, the duration of treatment and the choice of route (topical or systemic) for treatment constitute factors interdependent Dosage and treatment regimen they will also depend on these factors just like the compound specific formula (I) used, the indication of the treatment, the ability of the compound of formula (I) to reach minimum inhibitory concentrations at the site of infection, the personal characteristics of the subject (such as weight), the compliance with the treatment regimen and the presence and severity of any adverse effects of the treatment.

Typically, for an adult human (with a weight of approximately 70 kilograms), is administered from 5 mg to 3,000 mg, more preferably 5 mg to 1,000 mg, more preferably from 10 mg to 100 mg, of compound of formula (I) at day through systemic administration. It is understood that these dose ranges are indicated by way of example only and that Daily administration can be adjusted based on the factors previous.

A preferred method of systemic administration It is oral. Individual doses of 10 mg to 1,000 are preferred mg, preferably 10 mg to 300 mg.

Topical administration can be used to deliver the compound of formula (I) systemically, or to Treat a subject locally. The amounts of compound of formula (I) to administer topically depend on factors such as skin sensitivity, type and location of the tissue to be treated, the composition and the vehicle (if exists) to be administered, the compound of formula (I) particular to be administered, as well as the particular disorder to be treated and the desired extent of systemic effects (not local).

For localized conditions, the topical administration For example, to treat an infection microbial of the eyes a formulation in the form of eye drops or spray that is applied directly to the eye affected. For the treatment of the cornea can also be formulated the compounds of the invention such as gels, drops or ointments, or they can be incorporated in collagen or in a polymeric screen hydrophilic Products can also be inserted as lenses contact or reservoirs or as a subconjunctival formulation. For the treatment of a microbial skin infection, the compound It is applied locally and topically in the form of gel, paste, ointment ointment For the treatment of oral infections, the compound It can be applied locally in the form of gel, paste, mouthwash or implant. In this way the treatment mode reflects the nature of the condition, being available in the art Formulations suitable for any selected route.

In the above, logically, the Compounds of the invention can be administered alone or as mixtures and compositions may also include other substances active or excipients as appropriate for the indication.

VII. Examples: Preparation of the compound

The following substructure and table show the compound structure of examples 1-38 prepared according to the procedures described below in the present memory The R or X groups used to illustrate the Examples of compounds are not necessarily related to respective R and X groups used to describe the different residues of formula (I) of the claims.

A. Synthesis of N-benzyl-3-hydroxypyridin-2-one preferred intermediate

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1-Benzyl-3-benzyloxy-1H-pyridin-2-one (Ghosh et al., J. Org. Chem. 1989, 54 , 5073) is dissolved in anhydrous methanol (10 ml) and a catalytic amount of Pd is added -C (0.1%) to the completely degassed solution. The mixture is hydrogenated under a hydrogen balloon until all the starting material is consumed. Once finished, the solution is filtered through Celite ™. The solvent is removed in vacuo and the residue is washed with ether to achieve the desired product.

1 H NMR (300 MHz, CDCl 3) δ 5.15 (s, 2H), 6.14 (t, J = 7.2 Hz, 1H); 6.71 (m, 1H), 7.31 (m, 6H), 9.07 (s, 1H).

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B. General procedure for the coupling of three components between pyridones, formaldehyde and amines : the pyridone intermediate of stage A (1 equiv.), HCHO or aldehyde (2.2 equiv.) Is mixed together in aqueous EtOH ( 10 ml) and stir for 30 minutes. Amine (2.2 equiv.) Is added, stirred for 12 hours and concentrated. The residue is dissolved in EtOH (10 ml) and purified by HPLC (water / acetonitrile / 0.1% TFA). The product is isolated as the TFA salt unless otherwise indicated. The yields are 75-95%.

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C. Examples 1-38 . Examples are prepared according to the above method by varying the amine. Example 36 is a comparative example.

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Example 1 1-Benzyl-3-hydroxy-4-piperidin-1-ylmethyl- 1H -pyridin-2-one

1 H NMR (300 MHz, CD 3 OD) δ 1.81 (m, 6H), 3.07 (m, 2H), 3.51 (m, 2H), 4.23 (s , 2H), 5.24 (s, 2H), 6.31 (d, J = 6.9 Hz, 1H), 7.35 (m, 6H); 19 F NMR (252 MHz, CD 3 OD) δ 85.5; 13C NMR (75 MHz, DMSO) δ 21.3, 22.7, 51.8, 52.5, 53.1, 106.4, 117.4, 127.7, 128.0, 128.2, 128.9, 137.3, 147.4, 158.0; ES MS (M + 1) 299.12; HRMS calculated for C 18 H 22 N 2 O 2, 298.38. Discovered (M + 1) 299.17.

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Example 2 1-Benzyl-3-hydroxy-4-morpholin-1-ylmethyl-1H-pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 3.25 (m, 4H), 3.81 (m, 4H), 4.18 (s, 2H), 5.17 (s, 2H), 6.31 (d, J = 6.9 Hz, 1H), 7.35 (m, 6H); 19 FNMR (300 MHz, DMSO) δ 88.5; 13 C NMR (300 MHz, DMSO) δ 51.6, 51.8, 53.4, 63.5, 107.9, 119.1, 127.8, 128.0, 128.2, 128.9, 137.3, 147.5, 158.3; ES MS (M + 1) 301.12; HRMS calculated for C 17 H 20 N 2 O 3, 300.35.

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Example 3 1-Benzyl-3-hydroxy-4-thiamorpholin-1-ylmethyl- 1 H -pyridin-2-one

1 HNMR (300 MHz, DMSO) δ 2.92 (m, 4H), 3.38 (m, 4H), 4.17 (s, 2H), 5.16 (s, 2H), 6 , 29 (d, J = 7.5 Hz, 1H), 7.34 (m, 6H), 9.97 (s, 1H); 19 F NMR (300 MHz, DMSO) δ 88.4; 13 C NMR (75 MHz, DMSO) δ 24.3, 51.9, 53.4, 53.7, 107.9, 110.9, 127.8, 128.0, 128.2, 128.8, 137.2, 147.6, 157.6; ES MS (M + 1) 317.14; HRMS calculated for C 17 H 20 N 2 O 2 S, 316.42. Discovered: (M + 1) 317.13.

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Example 4 1-Benzyl-3-hydroxy-4-thiazolidin-1-ylmethyl- 1 H -pyridin-2-one

1 HNMR (300 MHz, DMSO) δ 3.09 (t, J = 6.3 Hz, 2H), 3.42 (t, J = 6.3 Hz, 2H), 4.03 (s , 2H), 4.29 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 10.48 (broad s, 1H); 19 FNMR (300 MHz, DMSO) δ 87.9; 13 CNMR (75 MHz, DMSO) δ 28.3, 48.3, 50.1, 56.3, 57.0, 107.4, 122.1, 127.8, 128.2, 128 , 8, 137.4, 146.3, 157.6; ES MS (M + 1) 303.08; Anal. calculated for C 18 H 19 N 2 O 4 SF, C, 51.92; H, 4.60; N, 6.73; S, 7.70. Discovered: C, 51.67; H, 4.48; N, 6.69; S, 7.65.

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Example 5 1-benzyl-4- (benzylaminomethyl) -3-hydroxy- 1 H -pyridin-2-one

1 HNMR (300 MHz, DMSO) δ 4.01 (s, 2H), 4.20 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7, 2 Hz, 1H), 7.36 (m, 11H), 9.16 (broad s, 1H); 19 FNMR (252 MHz, DMSO) δ 88.6; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 321.16; Anal. Calcd. For C 22 H 21 F 3 N 2 O 4, C, 60.83; H, 4.87; N, 6.45. Discovered: C, 60.75; H, 4.56; N, 6.34.

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Example 6 1-Benzyl-3-hydroxy-4 - [(2-pyridin-2-ylethylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 3.26 (m, 2H), 3.37 (m, 2H), 4.08 (s, 2H), 5.17 (s, 2H); 6.34 (d, J = 7.2 Hz, 1H), 7.38 (m, 6H), 7.86 (d, J = 5.7 Hz, 2H), 8.84 (m, 2H), 9.32 (broad s, 1H); 19 FNMR (252 MHz, DMSO) δ 88.6; 13 C NMR (75 MHz, DMSO) δ 31.5, 44.1, 46.3, 51.8, 106.9, 114.8, 127.1, 128.1, 128.8, 137.4, 143.8, 146.1, 155.3, 157.5, 158.4; ES MS (M + 1) 336.18; HRMS calculated for C 20 H 21 N 3 O 2, 335.40. Discovered: 336.16.

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Example 7 1-Benzyl-3-hydroxy-4-pyrrolidin-1-ylmethyl- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.96 (s, 4H), 3.16 (s, 2H), 3.43 (s, 2H), 4.23 (s, 4H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 88.7; 13 C NMR (75 MHz, DMSO) δ 22.8, 50.9, 51.8, 53.7, 107.3, 118.0, 128.0, 128.2, 128.9, 137.3, 146.7, 157.6; ES MS (M + 1) 285.13; Anal. Calcd. For C 19 H 21 F 3 N 2 O 4, C, 57.28; H, 5.31; N, 7.03. Discovered: C, 57.10; H, 5.11, N, 7.02.

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Example 8 1-Benzyl-4- (4-benzylpiperdin-1-ylmethyl) -3-hydroxy- 1 H -pyridin-2-one

1 H NMR (DMSO) δ 1.43 (m, 2H), 1.72 (m, 4H), 2.96 (m, 2H), 3.41 (m, 3H), 4.09 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.35 (m, 11H); 19 F NMR (252 MHz, DMSO) 88.8; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 389.21; HRMS calculated for C 25 H 28 N 2 O 2, 388.50. Discovered (M + 1) 389.22.

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Example 9 1-benzyl-4- (4-benzylpiperacin-1-ylmethyl) -3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 3.11 (broad s, 4H), 3.81 (s, 2H), 4.18 (s, 2H), 5.15 (s, 2H) , 6.24 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 7.46 (m, 5H); 19 F NMR (252 MHz, DMSO) δ 88.2; 13C (75 MHz, DMSO) δ; ES MS (M + 1) 390.21; HRMS calculated for C 24 H 27 N 3 O 2, 389.49. Discovered (M + 1) 390.21.

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Example 10 1-benzyl-3-hydroxy-4- (3-hydroxypyrrolidin-1-ylmethyl) - 1 H -pyridin-2-one

1 HNMR (300 MHz, DMSO) δ 1.90 (m, 1H), 3.18 (m, 2H), 3.47 (m, 3H), 4.24 (s, 2H), 4 , 43 (s, 1H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 89.0; 13 C NMR (75 MHz, DMSO) δ 51.8, 52.6, 61.3, 68.6, 107.4, 117.9, 128.0, 128.2, 128.9, 137.3, 146.7, 157.6; ES MS (M + 1) 301.13; HRMS calculated for C 17 H 20 N 2 O 3, 300.35. Discovered: (M + 1) 301.15.

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Example 11 1-Benzyl-4 - [([1,3] dioxolan-2-ylmethylmethylamino) methyl] -3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 2.81 (s, 3H), 3.35 (d, J = 3.9 Hz, 2H), 3.89 (m, 2H), 4, 01 (m, 2H), 4.21 (m, 2H), 5.17 (s, 2H); 5.27 (t, J = 3.9 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 7.35 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 88.5; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 331.18; HRMS calculated for C 18 H 22 N 2 O 4, 330.38. Discovered (M + 1) 331.16.

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Example 12 1-benzyl-3-hydroxy-4 - {[(tetrahydrofuran-2-ylmethyl) amino] methyl} -1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.56 (m, 1H), 1.86 (m, 2H), 1.99 (m, 1H), 2.92 (m, 1H), 3.05 (m, 1H), 3.80 (m, 2H), 4.09 (m, 3H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H ), 7.34 (m, 6H); 8.91 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.5; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 315.16; HRMS Calcd for C 18 H 22 N 2 O 3, 314.38. Discovered (M + 1) 315.16.

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Example 13 1-Benzyl-3-hydroxy-4 - [(2-methoxyethylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 3.13 (broad s, 2H), 3.30 (s, 3H), 3.59 (t, J = 5.4 Hz, 2H), 4 , 02 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 8.91 (broad s, 1H ); 19 F NMR (252 MHz, DMSO) δ 88.4; 13 C NMR (252 MHz, DMSO) δ; ES MS (M + 1) 289.13; HRMS calculated for C 16 H 20 N 2 O 3, 288.34. Discovered (M + 1) 289.15.

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Example 14 1-Benzyl-4- (1,4-dioxa-8-azaspiro [4,5] dec-8-ylmethyl) -3-hydroxy- 1H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.90 (m, 4H), 3.11 (m, 2H), 3.43 (m, 2H), 3.93 (s, 4H), 4.19 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 10.01 (broad s, 1 HOUR); 19 F NMR (252 MHz, DMSO) δ 88.3; 13 C NMR (75 MHz, DMSO) δ 31.7, 50.7, 51.9, 52.5, 64.5, 101.1, 108.0, 116.5, 127.8, 128.0, 128.3, 128.9, 137.3, 147.5 157.6; ES MS (M + 1) 357.19; HRMS calculated for C 20 H 24 N 4 O 2, 356.42. Discovered (M + 1) 357.18.

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Example 15 4-acepan-1-ylmethyl-1-benzyl-3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.61 (m, 4H), 1.80 (m, 4H), 3.20 (m, 4H), 4.17 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 88.9; 13 C NMR (75 MHz, DMSO) δ 22.8, 26.4, 51.8, 53.4, 54.4, 107.6, 117.2, 127.9, 128.0, 18.2, 128.9, 137.3, 147.2, 157.6; ES MS (M + 1) 313.18; HRMS calculated for C 19 H 24 N 2 O 4, 312.41. Discovered (M + 1) 313.19.

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Example 16 4-azocan-1-ylmethyl-1-benzyl-3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.59 (m, 10H), 3.18 (m, 2H), 3.38 (m, 2H), 4.17 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 88.9; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 327.2; HRMS calculated for C 20 H 26 N 2 O 2, 326.43. Discovered (M + 1) 327.20.

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Example 17 1-benzyl-4- {1,4 '] - bipiperidinyl-1'-ylmethyl-3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.43-1.98 (m, 10H), 2.21 (m, 2H), 3.01 (m, 4H), 3.43 (m , 3H), 4.12 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 9.85 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.7; 13 C NMR (75 MHz, DMSO) δ 21.6, 22.9, 23.8, 49.6, 50.5, 51.8, 53.0, 59.5, 108.0, 127.8, 128.0, 128.2, 128.9, 137.3, 147.5, 157.6; ES MS (M + 1) 382.4; HRMS calculated for C 23 H 31 N 3 O 2, 383.51. Discovered (M + 1) 382.25.

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Example 18 1-benzyl-4- (3,4-dihydro-2H-quinolin-1-ylmethyl) -3-hydroxy- 1H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 3.13 (t, J = 6.3 Hz, 2H), 3.52 (m, 2H), 4.28 (s, 2H), 4, 41 (s, 2H), 5.18 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.23-7.41 (m, 10H), 10.15 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.9; 13 C NMR (75 MHz, DMSO) δ 25.4; 49.3, 51.8, 52.7, 52.9, 107.6, 11.6, 116.8, 126.9, 127.0, 127.9, 128.0, 128.1, 128, 2, 128.8, 128.9, 131.7, 137.3, 147.3, 157.6; ES MS (M + 1) 347.40; HRMS calculated for C 22 H 22 N 2 O 2, 346.42. Discovered (M + 1) 347.17.

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Example 19 Benzyl Acid Ester 1- (1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-ylmethyl) pyrrolidin-2-carboxylic acid

1 H NMR (300 MHz, .DMSO) δ 2.01 (m, 3H), 2.45 (m, 1H), 3.26 (m, 1H), 3.53 (m, 1H), 3.69 (s, 3H), 4.30 (m, 3H), 5.17 (s, 2H), 6.27 (d, 6.9 Hz, 1H), 7.35 (m, 6H), 19 F NMR (252 MHz, DMSO) δ 88.3; 13C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 343.20; HRMS calculated for C 19 H 22 N 2 O 4, 342.39. Discovered (M + 1)

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Example 20 1-Benzyl-3-hydroxy-4 - [(2-hydroxy-1,1-dimethylethylamino) methyl] -1H- pyridin-2-one

1 H NMR (300 MHz, DMSO) d 1.27 (s, 6H), 3.49 (s, 2H), 3.95 (s, 2H), 5.17 (s, 2H), 6 , 34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 8.47 (broad s, 2H), 9.94 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.7; 13C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 303.19; HRMS calculated for C 17 H 22 N 2 O 3, 302.37. Discovered (M + 1) 303.17.

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Example 21 1-benzyl-3-hydroxy-4 - {[(pyridin-4-ylmethyl) amino] methyl} -1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 4.07 (s, 2H), 4.32 (s, 2H), 5.16 (s, 2H), 6.34 (d, J = 7 , 2 Hz, 1H), 7.34 (m, 6H); 7.62 (d, J = 5.7 Hz, 2H), 8.71 (d, J = 4.5 Hz, 2H); 19 F NMR (252 MHz, DMSO) δ 88.0; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 322.17; HRMS calculated for C 19 H 19 N 3 O 2, 321.37. Discovered (M + 1) 322.15.

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Example 22 1-Benzyl-3-hydroxy-4- (2-methoxymethylpyrrolidin-1-ylmethyl) - 1 H -pyridin-2-one

1H NMR (300 MHz, DMSO) δ 1.71 (m, 1H), 1.84 (m, 1H), 1.99 (m, 1H), 2.15 (m, 1H), 3.19 ( m, 1H), 3.30 (s, 3H), 3.41 (m, 1H), 3.62 (m, 2H), 3.77 (m, 1H), 4.15 (m, 1H), 4.39 (m, 1H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H); 9.60 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.3; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 329.2; HRMS calculated for C 19 H 24 N 2 O 3, 328.41. Discovered (M + 1)

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Example 23 1-benzyl-4 - {[(furan-2-ylmethyl) amino] methyl} -3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 4.00 (s, 2H), 4.28 (s, 2H), 5.16 (s, 2H), 6.27 (d, J = 6 , 9 Hz, 1H), 6.54 (m, 1H), 6.65 (m, 1H), 7.34 (m, 6H), 7.80 (m, 1H), 9.27 (broad s, 1 HOUR); 19 F NMR (252 MHz, DMSO) δ 88.3; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 323.15; HRMS calculated for C 18 H 18 N 2 O 3, 310.35. Discovered (M + 1)

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Example 24 1-Benzyl-3-hydroxy-4 - [(2-methylsulfanylethylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 2.10 (s, 3H), 2.74 (t, J = 6.9 Hz, 2H), 3.16 (t, J = 8.1 Hz, 2H), 4.05 (s, 2H), 5.17 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 7.34 (m, 6H), 19F NMR (252 MHz, DMSO) δ 89.0; ES MS (M + 1) 305.14, HRMS calculated for C 16 H 20 N 2 O 2 S, 304.41. Discovered (M + 1)

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Example 25 1-benzyl-3-hydroxy-4- (2-pyridin-2-ylpyrrolidin-1-ylmethyl) - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 2.12 (m, 4H), 3.39 (m, 1H), 3.63 (m, 1H), 4.07 (m, 2H), 4.60 (m, 1H), 5.10 (m, 2H), 6.15 (d, J = 6.9 Hz, 1H), 7.33 (m, 6H), 7.44 (m, 1H ), 8.05 (d, J = 8.1 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.74 (s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.0; ES MS (M + 1) 362.22; HRMS calculated for C 22 H 23 N 3 O 2, 361.44. Discovered (M + 1)

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Example 26 1-Benzyl-3-hydroxy-4 - [(4-methoxybenzylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 Mhz, DMSO) δ 3.70 (s, 3H), 3.98 (s, 2H), 4.13 (s, 2H), 5.16 (s, 2H), 6.28 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 9.0 Hz, 4H), 7.34 (m, 6H); 9.07 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 89.0; ES MS (M + 1) 351.10; HRMS calculated for C 21 H 22 N 2 O 3, 350.41. Discovered (M + 1) 351.17.

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Example 27 1-Benzyl-3-hydroxy-4 - [(1-phenylethylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.59 (d, J = 7.2 Hz, 3H), 3.71-3.93 (m, 2H), 4.45 (m, 1H ), 5.15 (s, 2H), 6.28 (d, J = 7.5 Hz, 1H), 7.34 (m, 11H); 19 F NMR (252 MHz, DMSO) δ 88.9; 13 C NMR (75 MHz, DMSO) δ 19.6, 42.5, 51.7, 58.0, 106.8, 119.3, 128.0, 128.1, 128.2, 128.9, 129.3, 129.4, 137.3, 145.9, 158.3; ES MS (M + 1) 335.13; HRMS calculated for C 21 H 22 N 2 O 2, 334.41. Discovered (M + 1) 335.17.

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Example 28 1-benzyl-4- [4- (6-chloropyridacin-3-yl) piperazin-1-ylmethyl] -3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 3.18 (m, 2H), 3.48 (m, 4H), 4.19 (s, 2H), 4.46 (m, 2H), 5.16 (s, 2H), 6.62 (d, J = 7.2 Hz, 1H), 7.35 (m, 6H), 7.48 (m, 1H), 7.68 (m, 1H ), 11.5 (broad s, 1H); 13 C NMR (75 MHz, DMSO) δ 42.1, 50.3, 51.9, 52.5, 108.2, 116.2; 118.0, 128.0, 128.2, 128.9, 129.8, 137.3, 147.4, 157.6, 158.8; ES MS (M + 1) 476.09. HRMS calculated for C 21 H 22 ClN 5 N 3 O 2, 411.88. Discovered (M + 1) 412.76.

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Example 29 1-Benzyl-3-hydroxy-4 - [(3-imidazol-1-ylpropylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 2.19 (m, 2H), 2.97 (m, 2H), 4.02 (s, 2H), 4.30 (t, J = 6 , 6 Hz, 2H); 5.17 (s, 2H), 6.30 (d, J = 6.9 Hz, 1H), 7.36 (m, 6H), 7.26 (s, 1H), 7.76 (s, 1H ), 9.03 (s, 1 H), 9.11 (s, 1 H); 19 F NMR (252 MHz, DMSO) δ 88.5; 13C NMR (75 MHz, DMSO) δ 26.5, 44.0, 46.0, 51.8, 106.8, 118.7, 120.5, 122.2, 127.9, 128.2, 128.9, 135.8, 137.4, 146.0, 158.2; ES MS (M + 1) 339.05; HRMS calculated for C 19 H 22 N 4 O 2, 338.44. Discovered (M + 1) 339.18.

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Example 30 1-benzyl-4-cycloheptylaminomethyl-3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.55 (m, 10H), 2.03 (m, 2H), 3.18 (s, 1H), 3.99 (m, 2H), 5.17 (s, 2H), 6.32 (d, J = 6.9 Hz, 1H), 7.35 (m, 6H), 8.65 (broad s, 2H), 9.98 (broad s , 1 HOUR); 19 F NMR (252 MHz, DMSO) d 88.6; 13 C NMR (75 MHz, DMSO) δ 23.0, 27.2, 30.4, 41.6, 51.7, 58.9, 107.0, 111.7, 127.9, 128.0, 128.2, 128.8, 137.4, 146.0, 157.5; ES MS (M + 1) 327.13; HRMS calculated for C 20 H 26 N 2 O 2, 326.43. Discovered (M + 1) 327.20.

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Example 31 1-Benzyl-3-hydroxy-4 - [(4-methylcyclohexylamino) methyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 0.93 (d, J = 6.9 Hz, 3H), 1.38 (m, 4H), 1.74 (m, 4H), 2, 05 (m, 1H), 3.10 (m, 1H), 4.01 (s, 2H), 5.17 (s, 2H), 6.31 (m, 1H), 7.34 (m, 6H ), 8.05 (broad s, 2H), 9.98 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.9; 13 C NMR (75 MHz, DMSO) δ; ES MS (M + 1) 327.14; HRMS calculated for C 20 H 26 N 2 O 2, 326.43; discovered (M + 1) 372.20.

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Example 32 1-Benzyl-4 - [(1-benzylpiperidin-4-ylamino) methyl] -3-hydroxy- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.77 (m, 2H), 2.31 (m, 2H), 2.98 (m, 2H), 3.30 (m, 3H), 3.46 (m, 2H), 4.03 (s, 2H), 0.29 (s, 2H), 5.16 (s, 2H), 6.30 (d, J = 7.5 Hz, 1H ), 7.34 (m, 6H), 7.49 (s, 5H), 9.12 (broad s, 1H), 10.05 (broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.8; 13 C NMR (75 MHz, DMSO) δ 27.1, 43.4, 51.8, 52.1, 54.2, 54.7, 57.6, 106.9, 118.5, 128.0, 128.1, 128.8, 129.3, 129.8, 130.7, 131.3, 137.3, 146.2, 157.4; ES MS (M + 1) 404.56; HRMS calculated for C 25 H 28 N 3 O 2, 403.52. Discovered (M + 1) 404.23.

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Example 33 3 - [(1-Benzyl-3-hydroxy-2-oxo-1,2-dihydropyridin-4-ylmethylamino] acepan-2-one

1 H NMR (300 MHz, DMSO) δ 1.25 (m, 1H), 1.59 (m, 2H), 1.74 (m, 1H), 1.92 (m, 1H), 2.10 (m, 1H), 3.18 (m, 3H), 4.03 (s, 2H), 4.2 (m, 1H), 5.17 (s, 2H), 6.33 (d , J = 7.5 Hz, 1H), 7.34 (m, 6H), 8.31 (t, J = 5.4 Hz, 1H), 9.07 (broad s, 2H), 9.90 ( broad s, 1H); 19 F NMR (252 MHz, DMSO) δ 88.4; 13 C NMR (75 MHz, DMSO) δ 27.0, 27.2, 28.4, 43.4, 51.7, 59.3, 107.1, 118.9, 127.8, 127.9, 128.1, 128.9, 137.4, 146.0, 157.5, 166.3; ES MS (M + 1) 342.01; HRMS calculated for C 19 H 23 N 3 O 3, 341.40. Discovered (M + 1) 342.18.

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Example 34 1-Benzyl-4 - [(1-benzylpyrrolidin-3-ylamino) methyl] -3-hydroxy-1H-pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 2.22 (m, 2H), 2.42 (m, 1H), 3.39 (m, 3H), 3.68 (m, 1H), 4.06 (s, 2H), 4.39 (s, 2H), 5.17 (s, 2H), 6.33 (d, J = 7.5 Hz, 1H), 7.30-7.52 (m, 11H); 19 F NMR (252 MHz, DMSO) δ 88.5; 13C NMR (75 MHz, DMSO) δ 27.1, 43.4, 51.8, 52.1, 54.2, 54.7, 57.5, 106.9, 118.5, 128.0, 128.8, 129.3, 129.8, 130.7, 131.3, 137.3, 146.2, 157.5; ES MS (M + 1) 390.14; HRMS calculated for C 24 H 27 N 3 O 2, 389.49. Discovered (M + 1) 390.21.

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Example 35 3-hydroxy-1- (3-methoxybenzyl) -4-pyrrolidin-1-ylmethyl- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.89 (m, 2H), 1.99 (m, 2H), 3.07 (m, 2H), 3.41 (m, 2H), 3.74 (s, 3H), 4.17 (m, 2H), 5.17 (s, 2H), 6.51 (d, J = 7.2 Hz, 1H), 6.90 (m, 3H ), 7.27 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 9.98 (broad s, 1H), 10.72 (broad s , 1 HOUR); 13 C NMR (75 MHz, DMSO) δ 23.0; 50.3, 51.7; 53.2; 55.4, 107.6, 113.2, 114.2, 118.2, 120.3, 127.8, 130.0, 18.8, 146.4, 157.6, 159.6; ES MS (M + 1) 315.82; HRMS calculated for C 18 H 22 N 2 O 3, 314.38. Discovered (M + 1) 315.17.

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Comparative example 36

3-hydroxy-1-pyridin-4-ylmethyl-4-pyrrolidin-1-ylmethyl- 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.81 (m, 4H), 3.05 (t, J = 6.0 Hz, 4H), 4.23 (s, 2H), 5, 48 (s, 2H), 6.76 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 6.6 Hz, 1H), 7.83 (d, J = 6.0 Hz, 2H), 8.89 (d, J = 6.0 Hz, 2H), 9.53 (broad s, 2H), 11.5 (broad s, 1H), 13 C NMR (75 MHz , DMSO) δ 22.7, 24.1, 44.5, 48.8, 50.1, 53.0, 108.2, 119.1, 125.3, 127.7, 42.1, 146 , 5, 156.7, 158.3; ES MS (M + 1) 286.99; HRMS calculated for C 16 H 19 N 3 O 2, 285.34. Discovered (M + 1) 286.15.

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Example 37 1-benzyl-3-hydroxy-4- [4- (2-methoxyphenyl) piperazin-1-ylmethyl] - 1 H -pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 2.95 (m, 2H), 3.30 (m, 2H), 3.48 (m, 4H), 3.80 (s, 3H), 4.25 (s, 2H), 5.18 (s, 2H), 6.34 (d, J = 7.2 Hz, 1H), 6.93 (m, 2H), 7.01 (m, 2H ), 7.34 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 88.5; 13C NMR (75 MHz, DMSO) δ 47.2, 51.8, 53.0, 55.3, 108.1, 112.2, 114.8, 116.2, 118.6, 121.2, 123.8, 127.8, 128.0, 128.9, 137.3, 139.6, 147.5, 152.2, 157.6; ES MS (M + 1) 405.82; HRMS calculated for C 24 H 27 N 3 O 3, 405.49. Discovered (M + 1) 406.21.

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Example 38 1-Benzyl-3-hydroxy-4 - [(1-phenylethyl-R-amino) methyl] -1H- pyridin-2-one

1 H NMR (300 MHz, DMSO) δ 1.58 (d, J = 6.9 Hz, 3H), 3.74 (m, 2H), 4.44 (m, 1H), 5, 14 (s, 2H), 6.23 (d, J = 7.2 Hz, 1H), 7.35 (m, 6H); 19 F NMR (252 MHz, DMSO) δ 89.4; 13 C NMR (75 MHz, DMSO) δ 19.6, 42.6, 51.7, 58.0, 106.9, 18.7, 128.0, 128.1, 128.8, 129.3, 129.4, 137.2, 137.4, 145.9, 157.5; ES MS (M + 1) 335.13; Anal. Calcd. For C 21 H 22 N 2 O 2, 334.41. Discovered (M + 1) 335.31.

Unless otherwise indicated, all quantities, including numbers, percentages, parts and proportions, it is understood that they are modified by the word "approximately" and amounts are not expected Indicate significant digits.

Unless otherwise indicated, the articles "un", "una" and "el", "la" mean "one or plus".

Claims (9)

1. A compound of formula (I) 18 in where:

to)

each R1 is independently selected from yes, hydrogen, halo, cyano, hydroxy, carboxy, keto, thiocete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

b)

each R2 is independently selected from yes, hydrogen, halo, cyano, hydroxy, carboxy, keto, thiocete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

C)

R 3 and R 4 are independently selected each other, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl and alkylheterocycloalkyl; or R 3 and R 4, together with the nitrogen atom to which they are attached, they bind to form heteroaryl or heterocycloalkyl moieties, optionally substituted with at least hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocyloalkyl and combinations thereof;

d)

R 5 and R 6 are independently selected each other, hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

and)

or isomers, diastereoisomers and optical enantiomers of the above formula, and pharmaceutically acceptable salts of the same.

2. The composition of claim 1, in the that each R2 is hydrogen. 3. The composition of claim 1 or the claim 2, wherein R 5 and R 6 are hydrogen. 4. The composition of claim 1, selected from: 1-benzyl-3-hydroxy-4-piperidin-1-ylmethyl-1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4-morpholin-1-ylmethyl-1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4-thiamorpholin-1-ylmethyl-1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4-thiazolidin-1-ylmethyl-1 H -pyridin-2-one; 1-benzyl-4- (benzylaminomethyl) -3-hydroxy- 1 H -pyridin-2-one; 1-Benzyl-3-hydroxy-4 - [(2-pyridin-2-ylethylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4-pyrrolidin-1-ylmethyl-1 H -pyridin-2-one; 1-benzyl-4- (4-benzylpiperdin-1-ylmethyl) -3-hydroxy- 1 H -pyridin-2-one; 1-benzyl-4- (4-benzylpiperacin-1-ylmethyl) -3-hydroxy- 1 H -pyridin-2-one; 1-Benzyl-3-hydroxy-4- (3-hydroxypyrrolidin-1-ylmethyl) - 1 H -pyridin-2-one-1-benzyl-4 - [([1,3] dioxolan-2-ylmethylmethyl-
mino) methyl] -3-hydroxy-1H-pyridin-2-one; 1-benzyl-3-hydroxy-4 - {[(tetrahydrofuran-2-ylmethyl) amino] methyl} -1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4 - [(2-methoxyethylamino) methyl] -1 H -pyridin-2-one; 1-Benzyl-4- (1,4-dioxa-8-azaespiro [4,5] dec-8-ylmethyl) -3-hydroxy- 1 H -pyridin-2-one-4-acepan-1-ylmethyl-1- benzyl-3-
hydroxy- 1 H -pyridin-2-one; 4-azocan-1-ylmethyl-1-benzyl-3-hydroxy- 1H -pyridin-2-one-1-benzyl-4- {1,4 '] - bipiperidinyl-1'-ylmethyl-3-hydroxy- 1H -
pyridin-2-one; 1-Benzyl-4- (3,4-dihydro-2H-quinolin-1-ylmethyl) -3-hydroxy- 1 H -pyridin-2-one; 1-Benzyl-3-hydroxy-4 - [(2-hydroxy-1,1-dimethylethylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4 - {[(pyridin-4-ylmethyl) amino] methyl} -1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4- (2-methoxymethylpyrrolidin-1-ylmethyl) -1 H -pyridin-2-one; 1-benzyl-4 - {[(furan-2-ylmethyl) amino] methyl} -3-hydroxy- 1 H -pyridin-2-one; 1-Benzyl-3-hydroxy-4 - [(2-methylsulfanylethylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4- (2-pyridin-2-ylpyrrolidin-1-ylmethyl) -1H -pyridin-2-one; 1-benzyl-3-hydroxy-4 - [(4-methoxybenzylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4 - [(1-phenylethylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-4- [4- (6-chloropyridacin-3-yl) piperazin-1-ylmethyl] -3-hydroxy- 1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4 - [(3-imidazol-1-ylpropylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-4-cycloheptylaminomethyl-3-hydroxy- 1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4 - [(4-methylcyclohexylamino) methyl] -1 H -pyridin-2-one; 1-benzyl-4 - [(1-benzylpiperidin-4-ylamino) methyl] -3-hydroxy- 1 H -pyridin-2-one-3 - [(1-benzyl-3-hydroxy-2-oxo-1,2 -
dihydropyridin-4-ylmethylamino] acepan-2-one; 1-benzyl-4 - [(1-benzylpyrrolidin-3-ylamino) methyl] -3-hydroxy- 1 H -pyridin-2-one; 3-hydroxy-1- (3-methoxybenzyl) -4-pyrrolidin-1-ylmethyl-1 H -pyridin-2-one; 3-hydroxy-1-pyridin-4-ylmethyl-4-pyrrolidin-1-ylmethyl-1 H -pyridin-2-one; 1-benzyl-3-hydroxy-4- [4- (2-methoxyphenyl) piperazin-1-ylmethyl] -1 H -pyridin-2-one; 1-benzyl-3- (benzylaminomethyl) -4-hydroxy- 1 H -pyridin-2-one; Y 1-benzyl-3-hydroxy-4 - [(1-phenylethyl-R-amino) methyl] -1 H -pyridin-2-one-5; 5. The use of a compound according to the claim 1 for manufacturing a pharmaceutical composition for treat a bacterial infection in a patient who needs it. 6. A pharmaceutical composition that understands:

to.

a safe and effective amount of a compound according to claim 1

b.

a pharmaceutically excipient acceptable.

7. A method of making a compound of formula IV:

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19

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in where:

to)

each R1 is selected from hydrogen, halo, cyano, hydroxy, carboxy, keto, thioacete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

b)

each R2 is selected from hydrogen, halo, cyano, hydroxy, carboxy, keto, thioacete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

which comprises the stages of:

(to)

supply a compound of formula II:

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twenty

quad

where each R2 is selected, independently of each other, of hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

(b)

protecting said compound of formula II with an agent alkylating agent in the presence of a base to form a compound of formula III:

twenty-one in where:

to)

R 1 and R 1 'are selected, independently of each other, of hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Y

b)

each R2 is independently selected from yes, hydrogen, halo, cyano, hydroxy, carboxy, keto, thiocete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Y

C)

selectively deprotect the compound from formula III with a hydrogenating agent to produce a compound of formula (IV).

8. The method of claim 7, which further comprises formulating with a formilant agent and laminating with an agent the compound of formula (IV) to produce a compound of formula (I): 22 in where:

to)

each R1 is independently selected from yes, hydrogen, halo, cyano, hydroxy, carboxy, keto, thiocete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

b)

each R2 is independently selected from yes, hydrogen, halo, cyano, hydroxy, carboxy, keto, thiocete, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl;

C)

R 3 and R 4 are independently selected each other, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylheteroalkyl, alkylaryl, alkylheteroaryl, alkylcycloalkyl and alkylheterocycloalkyl; or R 3 and R 4, together with the nitrogen atom to which they are attached, they bind to form heteroaryl or heterocycloalkyl moieties, optionally substituted with at least hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocyloalkyl and combinations thereof;

d)

R 5 and R 6 are independently selected each other, hydrogen, halo, cyano, hydroxy, carboxy, keto, thioaceto, amino, acylamino, acyl, amido, phenyl, aryloxy, alkyl, alkenyl, alkynyl, heteroalkyl, halo, haloalkyl, alkoxy, aryl, heteroaryl, cycloalkyl and heterocycloalkyl.

9. The method of claim 8, wherein each and every one of the R 2, R 5 and R 6 of the compound of Formula (I) are hydrogen.